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Samuel Coulbourn Flores, Nucleic acids research, September 29 (2013)  View

Determining the conformational rearrangements of large macromolecules is challenging experimentally and computationally. Case in point is the ribosome; it has been observed by high-resolution crystallography in several states, but many others are known only from low-resolution methods including cryo-electron microscopy. Combining these data into dynamical trajectories that may aid understanding of its largest-scale conformational changes has so far remained out of reach of computational methods. Most existing methods either model all atoms explicitly, resulting in often prohibitive cost, or use approximations that lose interesting structural and dynamical detail. In this work, I introduce Internal Coordinate Flexible Fitting, which uses full atomic forces and flexibility in limited regions of a model, capturing extensive conformational rearrangements at low cost. I use it to turn multiple low-resolution density maps, crystallographic structures and biochemical information into unified all-atoms trajectories of ribosomal translocation. Internal Coordinate Flexible Fitting is three orders of magnitude faster than the most comparable existing method.

Related Publications
A trajectory of ribosomal translocation with Internal Coordinate Fitting, SC Flores, in preparation (2012)

Due to a flurry of activity over the past decade, much has been learned of the structure of the ribosome. It has been observed by high resolution crystallography in several states but much dynamical information is missing, in particular for the crucial process of translocation. Clues are available in the form of biochemical results and low-resolution Cryo-Electron Microscopy densities. In this work we show how an internal coordinate approach can economically turn multiple low-resolution density maps and biochemical information into a unified all-atoms trajectory of ribosomal translocation. The results demonstrate a widely applicable semiflexible fitting algorithm and yield new insight into the process of ribosomal translocation.